General summary

Background

Diabetes mellitus is a chronic disorder of glucose metabolism and is
the single biggest cause of preventable blindness, the leading cause of
non-traumatic lower extremity amputation and a major cause of end-stage
renal disease and coronary heart disease in European populations. The
lifetime cumulative incidence of diabetes in European populations is
35-40%, it is a major cause of premature mortality and accounts for
5-10% of health care expenditure. The prevalence of diabetes is rising
in European populations and thus efforts to understand the aetiology of
the condition and develop preventive strategies are key public health
targets.

The overall importance of environmental factors in the aetiology of
type 2 diabetes is evidenced by observations of increased diabetes risk
among individuals from at-risk populations who migrate to countries
where lifestyles are more westernised and from cohort studies where the
importance of major non-genetic risk factors such as obesity, physical
inactivity, and dietary intake of fat have been demonstrated. The
strength of causal inference concerning these aetiological factors is
high, not only because findings have been replicated in many studies in
different populations, but also because interventions aimed at changing
these factors have led to reductions in the incidence of diabetes in
randomised controlled trials. The importance of genetic factors in
leading to type 2 diabetes has been demonstrated by studies of familial
aggregation, high concordance in twin studies and the impact of
different degrees of high-risk heritage on diabetes risk in high
prevalence populations. Progress in discovering the genetic basis of
diabetes is accelerating as more powerful genotyping technologies are
applied to larger study samples.

The global variation in the prevalence of type 2 diabetes is marked and
suggests that an interaction between genes and lifestyles in central to
determining diabetes risk. The geographical pattern of variation
suggests that prevalence is lowest in rural areas of developing
countries, is generally intermediate in developed countries, but is
highest in certain ethnic groups who have adopted western lifestyle
patterns. One explanation for this variation is the "thrifty genotype"
hypothesis which postulates that genetic variation which was
advantageous in times of food scarcity would become disadvantageous in
times of food abundance. The human genome, tailored to function in a
hostile environment, now faces novel stressors, and depending on the
genetic subgroup, copes variably with this challenge. The InterAct
project is aimed at investigating the basis of these interactions.